Cellular Responses
to Stress and Toxic
Insults
Homeostasis
Maintenance of the body’s healthy steady
state
CELL INJURY
CAUSES
Hypoxia (O2 Deprivation)
•Cardio-respiratory failure
(inadequate oxygenation in blood)
•Ischemia (reduced blood flow)
•Anemia (decreased O2 carrying capacity
of blood)
•CO poisoning
•Severe blood loss
Physical Agents
•Mechanical trauma
•Extreme temperature (burns or cold
environment)
•Sudden changes in atmospheric
pressure
•Radiation
•Electric shock
Chemical Agents and Drugs
•Hypertonic solution (cause swelling of
cells)
•Poisons (cyanide or mercury)
•Environmental Pollutants
•Insecticides and herbicides
•Industrial and occupational hazards
•Recreational and Therapeutic (toxic
side effects) drugs
Infectious Agents
•Viruses, Fungi, Bacteria, Parasites
Immunologic Reactions
•Endogenous self-antigens (autoimmune
•Immune reactions to external agents
Genetic Abnormalities
•Extra chromosome (Down Syndrome)
•Amino acid substitution (Sickle Cell
Anemia)
•Congenital malformations
•Genetic defects
Nutritional Imbalances
•Protein Calorie Deficiencies
•Vitamin Deficiencies
•Nutritional Excess (Obesity)
Cell Adaptation
•First response to injurious
stimuli
•Reversible
-(seen in physiologic and
pathologic states)
REVERSIBLE
Mild and transient
IRREVERSIBLE
Severe and progressive
“Point of no return”
Necrosis
Apoptosis
Progression is not ACUTE
•Due to lag time between the
injurious stimuli and cell death
•Early removal = revert to normal
Persistent injury
•EARLY changes: Biochemical and
ultrastructural changes
•LATER changes: Light microscopic
and gross morphologic changes
Mechanisms of Cell Injury
•Cellular responses to
injurious stimuli depend on:
-Type
-Duration
-Severity of injury
•Consequences of cell injury
will depend on:
-Type
-State
-Adaptability of injured cell
Mitochondrial Damage
•3 MAJOR CONSQUENCES
-ATP depletion
-Formation of ROS (incomplete phosphorylation)
-Initiation of apoptosis (leakage of Bac or Bax)
of necrosis
Membrane Damage
•4 MECHANISMS
-Presence of ROS (lipid peroxidation)
-Decreased phospholipid synthesis
(defective mitochondrial function or hypoxia)
-Increased phospholipid breakdown
-Cytoskeletal abnormalities (due to
activation of proteases which increases cytosolic Ca+2)
DNA Damage
•4 MECHANISMS
-DNA damage
-Activation of p53 (impairment of the pathway increases
the risk for cancer)
-Initially stop the cell cycle (G1) to allow
DNA repair
-Apoptosis (Intrinsic/Mitochondrial
Pathway) (Happens when repair mechanisms fail)
Endoplasmic Reticulum Stress
•Accumulation of unfolded or misfolded proteins
= ER adaptive mechanisms stress —> APOPTOSIS
2 FEATURES SEEN
•Generalized swelling
-Caused by failure of ATP-dependent
Na-K pump (ATP depletion)
-Presence of surface bleb or
ballooning out
-Increased eosinophilia in cytoplasm
-Detachment of ribosome from ER
-Clumping of nuclear chromatin
-Influx of water
•Fatty change (Steatosis)
-Seen in organs actively involved in
lipid metabolism (LIVER)
-Accumu ation of TRIGLYCERIDES
within vacuoles
-Liver cells with lipid-filled vacuoles in
the cytoplasm with nucleus in the
periphery
•Accidental cell death (due to ischemia,
toxins, burns, leakage of activated
proteases)
•Mechanisms:
-Denaturation of cellular proteins (due
to proteases)
-Leakage of cellular contents
(damaged membranes)
-Enzymatic digestion of injured cell.
•LOCAL INFLAMMATION (Always present)
PATHOLOGIC FINDINGS
•Increased eosinophilia
•Glassy, homogenous appearance
•Vacuolated, moth-eaten cytoplasm
•Myelin figures (phospholipid
precipitates that cannot be
phagocytized)
•Calcifications
NUCLEAR CHANGES
(1-2 days)
•PYKNOSIS: nuclear shrinkage,
increased basophilia, chromatin
condensation
•KARYORRHEXIS: fragmented
pyknotic nucleus
•KARYOLYSIS: dissolution of nucleus
due to endonucleases
PATTERNS OF TISSUE
NECROSIS
COAGULATIVE NECROSIS (INFARCT)
•CAUSES: Ischemia or obstruction of a vessel
•Architecture of the dead tissue is preserved
(presence of blebs or denatured cells)
-Wedge-shaped with tissue appearing to
have firm texture
•Nucleus is ABSENT
•ALL tissue and solid organs can be affected
EXCEPT BRAIN
LIQUEFACTIVE NECROSIS
•CAUSES: Focal bacterial or fungal infections
•Dissolution of the tissue due to leukocytic
release of enzymes
•Transformation of tissue into a viscous
fluid (pus—creamy yellow = dead cells +
neutrophils)
•Usually occurs in the BRAIN
GANGRENOUS NECROSIS
•CAUSES: Loss of blood supply of a tissue
(usually lower limb)
•Not a specific pattern as it can happen to any
tissue
•Dry Gangrene: more associated with
coagulative necrosis
•Wet Gangrene: more associated with
liquefactive necrosis
CASEOUS NECROSIS
•CAUSES: Commonly seen in foci of tuberculous
infection (may also be present in silicosis,
sarcoidosis, fungal infections)
•Cheeselike— friable white appearance
•Histologic Findings:
-Granuloma: necrotic (pale/no cells)
-Lym phoc yte inf ilt rate s
-Fused macrophages/Multinucleated giant
cells:
•Langhans type: more associated with
TB; horseshoe-shaped nucleus
•Foreign Body type: nucleus is spread
out in the entire cell mass
FAT NECROSIS
•CAUSES: Acute pancreatitis
•Form of coagulative necrosis
•Chalky, white spot (fat saponification— fatty
acids + calcium)
•Due to release of activated pancreatic lipases
•Histologic Findings: necrotic fat cells,
basophilic calcium deposits, inflammatory
reaction
FIBRINOID NECROSIS
•CAUSES: Vascular damage usually seen in
immune reactions involving blood vessels
•Ag-Ab complexes deposition in the walls of
arteries + leaked out plasma proteins =
fibrinoid (fibrin-like) appearance— bright
pink, amorphous appearance
Tightly regulated suicide program/cell death
•End result: removal of damaged cells by
macrophages
•Mechanisms:
-Activation of CASPASES (marker for the start
of apoptotic process)
-ProteASES that contains Cysteine in their
active site and cleave proteins after ASPartic
residues
•NO LOCAL INFLAMMATION (Enzymes does not
leak out before cell death)
CAUSES
PHYSIOLOGIC
•Removal of supernumerary cells
(senescent)
•Involution of hormone-dependent tissues
(e.g., endometrium, ovary, breast)
•Cell turnover and death of host cells that
have served their purpose (e.g., neutrophil
after an inflammatory response)
•Elimination of self-reactive lymphocytes
CAUSES
PATHOLOGIC
•DNA damage
•Accumulation of misfolded proteins
•Infections
•Pathologic atrophy (duct
obstruction)
Morphologic and Biochemical
Changes
•Cell shrinkage
•Chromatin condensation
•Formation of cytoplasmic blebs
and apoptotic bodies
•Phagocytosis by macrophages
PHASES OF APOPTOSIS
Initiation Phase
Mitochondrial (Intrinsic) Pathway
•Responsible for apoptosis in most physiologic and
pathologic situation.
•Release of CYTOCHROME C (pro-apoptotic
molecule in mitochondria)
-Smac/DIABLO: pro-apoptotic; mitochondrial;
inhibits function of IAPs (physiologic
inhibitor of apoptosis)
-FLIP: anti-apoptotic; binds to procaspase-8
(no activation of caspases)
•BCL-2: anti-apoptotic gene that reside in the outer
mitochondrial membrane, cytosol, and ER; prevents
the release of cytochrome C; expressed in B-cell
lymphoma
•Cytochrome C will bind to Apaf-1 (Apoptosis
Activating Factor-1) to form APOPTOSOME
•Cytochrome C-Apaf-1 complex bind and activate
CASPASE-9 —> CASPASE 3 —> CASPASE 7
(execution phase)
Death Receptor (Extrinsic) Pathway
•Engagement of PLASMA MEMBRANE
death receptor
•Mediated by TNF receptor family
-TNFR1
-Fas (CD95): expressed in T cell; 3 or
more molecules of Fas bound
together form FADD/ Fas-associated
death domain protein
•FADD: activates CASPASE 8 (initiate
execution phase)
Execution Phase
•Activated by either intrinsic or
extrinsic pathways
•END RESULT: Activation of
Caspase-3 and 7
•EFFEROCYTOSIS
-Removal of dead cells
-Apoptotic body breaks down into
fragments edible for phagocytes
Anti-apoptotic
Factors
•BCL-2
•BCL-XL
•MCL-1
•BH1-4
Pro-
apoptotic
Factors
•BAX
•BAK
•BH1-3
Regulated
Apoptosis Initiators
•BAD
•BIM
•BID
•PUMA
•NOXA
•BH3 only
proteins
